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Synthesis and properties of chemotactic peptide analogs. II. HCO-Met-Leu-Phe-OMe analogs containing cyclic alpha,alpha-disubstituted amino acids as Met and Phe mimicking residues. 趋化肽类似物的合成及性质。2含有环α, α -二取代氨基酸作为Met和Phe模拟残基的HCO-Met-Leu-Phe-OMe类似物。
I Torrini, G Pagani Zecchini, M Paglialunga Paradisi, G Lucente, E Gavuzzo, F Mazza, G Pochetti, S Spisani, A L Giuliani

As a part of a research program aimed at studying structure activity relationship in the field of chemotactic peptides, modified analogs of the potent chemoattractant HCO-Met-Leu-Phe-OH (fMLP) of the general formula HCO-Xaa-Leu-Yaa-OMe are examined. 4-Aminotetrahydrothiopyran-4-carboxylic acid (Thp) and 2-aminoindane-2-carboxylic acid (Ain) have been chosen as achiral, conformationally restricted amino acids suitable to mimick the external Met and Phe residues of fMLP-OMe. Studies on a first model, namely [Ain3]fMLP-OMe 1, have already been reported (12). Here the two remaining analogs [Thp1, Ain3] 2 and [Thp1] 3 have been synthesized. The conformation in the crystal of the disubstituted analog 2 has been determined and compared with those adopted by the parent fMLP-OMe and by previously studied models. The backbone conformation of 2 is characterized by helical folding centred at each of the three residues with the central Leu presenting helical handedness opposite to those of the two adjacent achiral residues. This conformation presents strong similarities with that adopted in the crystal by fMLP-OMe and resembles the conformation of fMLP bound to immunoglobulin (Bence-Jones dimer). The conformationally restricted analogs 2 and 3 are more active than the parent in the stimulation of directed mobility of human neutrophils but are practically inactive in the superoxide production. Crystals of 2 are orthorhombic, s.g. P2(1)2(1)2(1), with a = 21.934 (8), b = 10.856 (2), c = 10.380 (2) A. The structure has been refined to R = 0.071 for 2301 independent reflections with I greater than 1.5 sigma.

作为研究趋化肽领域结构活性关系的研究计划的一部分,研究了通式HCO-Xaa-Leu-Yaa-OMe的强效趋化剂hco - met - leu - pheoh (fMLP)的修饰类似物。选择了4-氨基四氢硫吡喃-4-羧酸(Thp)和2-氨基吲哚-2-羧酸(Ain)作为适合模拟fMLP-OMe外部Met和Phe残基的非手性构象限制性氨基酸。对第一种模型[Ain3]fMLP-OMe 1的研究已经有报道(12)。本文合成了剩下的两个类似物[Thp1, Ain3] 2和[Thp1] 3。确定了双取代类似物2的晶体构象,并与母体fMLP-OMe和先前研究的模型采用的构象进行了比较。2的主链构象的特点是以三个残基为中心的螺旋折叠,中心Leu呈现与相邻的两个非手性残基相反的螺旋手性。这种构象与fMLP- ome在晶体中采用的构象非常相似,类似于fMLP与免疫球蛋白(bince - jones二聚体)结合的构象。构象限制性类似物2和3在刺激人类中性粒细胞的定向迁移方面比亲本更活跃,但在超氧化物的产生方面实际上是不活跃的。2的晶体为正交晶型,如P2(1)2(1)2(1), a = 21.934 (8), b = 10.856 (2), c = 10.380 (2) a。对于2301个独立反射,I大于1.5 sigma,结构细化为R = 0.071。
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引用次数: 0
A CD strategy for the study of polypeptide folding/unfolding. A synthetic foot-and-mouth disease virus immunogenic peptide. 用于多肽折叠/展开研究的CD策略。一种合成的口蹄疫病毒免疫原肽。
G Siligardi, A F Drake, P Mascagni, D J Rowlands, F Brown, W A Gibbons

The circular dichroism spectrum of the 20-residue immunogenic peptide from the foot-and-mouth disease virus (VP1; 141-160 of serotype A, subtype 12) was solvent- and temperature-dependent. Careful solvent titration revealed two isodichroic points and plateaux consistent with stepwise unfolding of specific stable conformations. Variable temperature studies in cryogenic solvents and urea perturbation were consistent with the existence of three conformational moieties, the left-handed extended helix, the alpha-helix, and the 3(10) helix. The number of residues in each helix was confirmed by CD spectral simulations. The strategy described here can be used to determine the components of a conformational equilibrium and their statistical weights, to study peptide folding and unfolding and to determine the bioactive conformation(s) of linear peptides. The conclusions were supported by 2D-NMR studies. A new mechanism for the stabilization of left-handed extended helices and destabilization of alpha-helices by urea is proposed. The structure of the peptide as resolved by CD spectroscopy is of particular significance since the conformation of this antigenic sequence in situ has so far not been solved by X-ray crystallography.

口蹄疫病毒(VP1) 20残基免疫原肽的圆二色谱分析血清型A的141-160,亚型12)依赖于溶剂和温度。仔细的溶剂滴定发现了两个等向色点和平台,与特定稳定构象的逐步展开一致。在低温溶剂和尿素扰动下的变温研究证实了三种构象的存在,即左旋扩展螺旋、α -螺旋和3(10)螺旋。通过CD谱模拟确定了每个螺旋中的残基数。这里描述的策略可用于确定构象平衡的组成部分及其统计权重,研究肽折叠和展开,并确定线性肽的生物活性构象。这些结论得到了二维核磁共振研究的支持。提出了左旋扩展螺旋稳定和α -螺旋被尿素破坏的新机制。由于该抗原序列的原位构象迄今尚未由x射线晶体学解决,因此用CD光谱解析的肽的结构具有特别重要的意义。
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引用次数: 0
Evidence for a beta-turn in an azadipeptide sequence. Synthesis and crystal structure of ButCO-Pro-AzaAla-NHPri. 偶氮二肽序列发生β转变的证据。ButCO-Pro-AzaAla-NHPri的合成及晶体结构。
Z Benatalah, A Aubry, G Boussard, M Marraud
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引用次数: 0
Conformational analysis of peptide surrogates. Reduced and retro-amide links in blocked alanine and in secondary structures. 肽替代物的构象分析。阻断丙氨酸和二级结构中的减少和反酰胺连接。
P Dauber-Osguthorpe, M M Campbell, D J Osguthorpe

We have investigated the conformational effects of modifying the amide link of peptides. We studied a reverse amide bond psi [NHCO], a reduced amide bond psi [CH2NH] and a retro-reduced bond psi [NHCH2] as surrogates for the amide link [CONH] in native peptides. A complete search of the conformational space available to residues with these modified links was carried out. The local minima and the rotational barriers were described and compared to the minima of the native residue. The results are compatible with the available observed structural data. These modified links have been incorporated in secondary structure units such as beta turns, alpha helices, and parallel and anti-parallel beta sheets. It was found that a reduced amide link can lead to stabilised beta turns, while the retro modification can be incorporated in stable beta sheets. A significant reduction in the stability of alpha helices is caused by the retro links, while a reduced amide link results in only a small destabilisation.

我们研究了修饰肽的酰胺键对构象的影响。我们研究了一个反酰胺键psi [NHCO],一个还原酰胺键psi [CH2NH]和一个还原酰胺键psi [NHCH2]作为天然肽中酰胺键[CONH]的替代品。对具有这些修饰链的残基的构象空间进行了完整的搜索。描述了局部极小值和旋转势垒,并与自然残差的极小值进行了比较。计算结果与现有的结构观测数据一致。这些改进的连杆已被纳入二级结构单元,如β匝、α螺旋、平行和反平行β片。研究发现,减少酰胺连接可以导致稳定的β转,而复古修饰可以纳入稳定的β片。α螺旋稳定性的显著降低是由复古连接引起的,而酰胺连接的减少只会导致小的不稳定性。
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引用次数: 0
Ten-membered cyclotripeptides. III. Synthesis and conformation of cyclo(-Me beta Ala-Phe-Pro-) and cyclo(-Me beta Ala-Phe-DPro-). 拥有cyclotripeptides。3环(- me β ala - ph - pro -)和环(- me β ala - ph - dpro -)的合成和构象。
S Cerrini, E Gavuzzo, G Lucente, G Luisi, F Pinnen, L Radics

The 10-membered cyclotripeptide cyclo(-Me beta Ala-Phe-Pro) 3 and its diastereoisomer cyclo(-Me beta Ala-Phe-DPro-) 4 have been synthesized under mild cyclization conditions starting from linear precursors containing C-terminal proline. The crystal and molecular structure of the two models has been determined by X-ray crystallography. Analysis of the NMR spectra supported by NOE data clearly indicates that the conformations found in the crystals are retained in solution. Both cyclotripeptides exhibit a cis-cis-trans backbone conformation. The two tertiary peptide bonds, at the proline and Me beta Ala nitrogen atoms, adopt a cis conformation whereas the CO-NH junctions are trans in both the models. The deviations from planarity of the peptide units vary from delta omega values of ca. 18 degrees for the Pro-Me beta Ala and DPro-Me beta Ala bonds to ca. 7 degrees for Phe-Pro and Phe-DPro bonds. Relevant conformational details of 3 and 4, as revealed by X-ray and NMR analysis, are reported. Crystals of 3 are monoclinic: P2(1), a = 5.317(2), b = 17.059(6), c = 9.514(3) A, beta = 99.18(3), Z = 2. The final R and Rw are 0.054 and 0.071 respectively. Crystals of 4 are orthorhombic: P2(1)2(1)2(1), a = 8.797(2), b = 19.440(9), c = 21.605(10) A, Z = 8. The final R and Rw are 0.069 and 0.104 respectively.

以含c端脯氨酸的线性前体为原料,在温和的环化条件下合成了10元环三肽cyclo(- me β ala - ph - pro) 3及其非对映异构体cyclo(- me β ala - ph - dpro -) 4。用x射线晶体学测定了两种模型的晶体和分子结构。NOE数据支持的核磁共振谱分析清楚地表明,在晶体中发现的构象在溶液中被保留。两种环三肽均呈顺-顺-反骨架构象。两个三级肽键,在脯氨酸和Me β - Ala氮原子上,采用顺式构象,而CO-NH连接在两种模型中都是反式的。肽单元与平面度的偏差从Pro-Me β Ala和DPro-Me β Ala键的δ ω值约18度到ph - pro和ph - dpro键的δ ω值约7度不等。通过x射线和核磁共振分析,报道了3和4的相关构象细节。3个晶体为单斜晶:P2(1), a = 5.317(2), b = 17.059(6), c = 9.514(3) a, β = 99.18(3), Z = 2。最终R和Rw分别为0.054和0.071。4个晶体为正交晶型:P2(1)2(1)2(1), a = 8.797(2), b = 19.440(9), c = 21.605(10) a, Z = 8。最终R和Rw分别为0.069和0.104。
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引用次数: 0
Stereocontrolled synthesis of psi[CH = CH] dipeptide isosteres. 立体控制合成psi[CH = CH]二肽同工异构体。
D J Kempf, X C Wang, S G Spanton

A new stereocontrolled synthesis of the psi[CH = CH] dipeptide isostere is described. They key step of the sequence relies on the stereospecific alpha-alkylation of delta-amino-gamma-mesyloxy-alpha,beta-unsaturated esters. The broad availability of nucleophilic alpha-side chains by this method allows the preparation of a wide variety of psi[CH = CH] isosteres with predictable stereochemistry.

介绍了一种新的立体控制合成psi[CH = CH]二肽同工异构体的方法。该序列的关键步骤依赖于δ -氨基- γ -甲氧基- α, β -不饱和酯的立体特异性烷基化。通过这种方法,亲核侧链的广泛可用性允许制备各种具有可预测立体化学性质的psi[CH = CH]同分异构体。
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引用次数: 0
Dimensional oscillation. A fast variation of energy embedding gives good results with the AMBER potential energy function. 维振荡。能量嵌入的快速变化使琥珀势能函数具有较好的效果。
M E Snow, G M Crippen

The structure of the AMBER potential energy surface of the cyclic tetrapeptide cyclotetrasarcosyl is analyzed as a function of the dimensionality of coordinate space. It is found that the number of local energy minima decreases as the dimensionality of the space increases until some limit at which point equipotential subspaces appear. The applicability of energy embedding methods to finding global energy minima in this type of energy-conformation space is explored. Dimensional oscillation, a computationally fast variant of energy embedding is introduced and found to sample conformation space widely and to do a good job of finding global and near-global energy minima.

分析了环四肽环四星基琥珀势能面结构与坐标空间维数的关系。发现局部能量极小值的数目随着空间维数的增加而减少,直到某一极限处出现点等势子空间。探讨了能量嵌入方法在这类能量构象空间中寻找全局能量最小值的适用性。一维振荡是能量嵌入的一种计算速度快的变体,它可以广泛地对构象空间进行采样,并能很好地寻找全局和近全局的能量极小值。
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引用次数: 0
Chemical synthesis of human beta-endorphin(1-27) analogs by peptide segment coupling. Leucine and glycine residues bearing thiocarboxyl functions as junctions for peptide segment coupling. 肽段偶联法合成人β -内啡肽(1-27)类似物。含有硫羧基的亮氨酸和甘氨酸残基作为肽段偶联的连接。
H C Cheng, D Yamashiro

[Gly8]beta hEP(1-27)NH2 and [L-Leu8]beta hEP(1-27)NH2, two analogs of human beta-endorphin, were synthesized by both all-stepwise solid phase synthesis and peptide segment coupling. For the peptide segment coupling method, two thiocarboxyl peptides. Msc-[Gly8]beta hEP(1-8)SH and Msc-[L-Leu8]beta hEP(1-8)SH, were synthesized by standard solid phase method on 4-[alpha-(Boc-Gly-S)benzyl]phenoxyacetamidomethy-resin and 4-[alpha-(Boc-L-Leu-S)benzyl]phenoxyacetamidomethy-resin. These two thiocarboxyl peptides were coupled to H-[Lys(Cit)9,19,24]-beta hEP(9-27)NH2. [Gly8]beta hEP(1-27)NH2 and [L-Leu8]beta hEP(1-27)NH2 were obtained after removal of Msc groups and citraconyl groups from products of the segment coupling reaction. The yields of both [Gly8]beta hEP(1-27)NH2 and [L-Leu8]beta hEP(1-27)NH2 in the segment coupling reaction were approximately 18%. Less than 1% of racemization of Leu-8 occurred during coupling of Msc-[L-Leu8]beta hEP(1-8)SH to H-[Lys(Cit)9,19,24]-beta hEP(9-27)NH2. Results of amino acid composition analysis, analysis by reverse phase high pressure liquid chromatography and receptor binding activity assays of the analogs showed that peptide analogs prepared by segment coupling method and those prepared by all-stepwise solid phase synthesis were identical. Results of receptor binding activity assays suggested that the molecular charge properties of beta-endorphin(1-27) and its analogs influenced the receptor binding activity.

[L-Leu8] β hEP(1-27)NH2和[L-Leu8] β hEP(1-27)NH2是人β -内啡肽的两种类似物,采用全步固相合成和肽段偶联的方法合成。对于肽段偶联法,两个硫代羧基肽。采用标准固相法在4-[α -(Boc-Gly-S)苄基]苯氧乙酰胺树脂和4-[α -(Boc-L-Leu-S)苄基]苯氧乙酰胺树脂上合成了Msc-[Gly8] β hEP(1-8)SH和Msc-[L-Leu8] β hEP(1-8)SH。这两个巯基肽偶联到H-[Lys(Cit)9,19,24]- β hEP(9-27)NH2上。从片段偶联反应产物中去除Msc基团和citraconyl基团后得到[Gly8] β hEP(1-27)NH2和[L-Leu8] β hEP(1-27)NH2。[L-Leu8] β hEP(1-27)NH2和[Gly8] β hEP(1-27)NH2在段偶联反应中的产率均约为18%。在Msc-[L-Leu8] β - hEP(1-8)SH与H-[Lys(Cit)9,19,24]- β - hEP(9-27)NH2偶联过程中,不到1%的Leu-8发生外消旋化。氨基酸组成分析、反相高压液相色谱分析和受体结合活性测定结果表明,片段偶联法制备的肽类似物与全步固相合成法制备的肽类似物完全相同。受体结合活性测定结果表明-内啡肽(1-27)及其类似物的分子电荷特性影响受体结合活性。
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引用次数: 0
Chemical modification of human growth hormone with N-acetylimidazole. Effect on binding capacity to lactogenic and somatogenic receptors. n -乙酰咪唑对人生长激素的化学修饰。对产乳和产体受体结合能力的影响。
P Kaliman, M R Ermácora, C Nowicki, C Wolfenstein-Todel, J A Santomé

The effect of acetylation of tyrosine residues on the binding capacity of human growth hormone (hGH) to rat liver lactogenic and somatogenic receptors was studied. When 3.7 tyrosine and 4.8 lysine residues were acetylated with N-acetylimidazole, both the in vivo and the in vitro capacities of hGH to compete with 125I-labeled bovine growth hormone for somatogenic binding sites greatly decreased. Acetylation also affected the in vitro binding capacity to lactogenic sites. Most of the somatogenic binding activity was recovered by hydroxylamine treatment, which removes O-acetyl groups from tyrosine residues but not N-acetyl groups from lysine residues. The same treatment partially restored lactogenic binding capacity. The reactivity of hGH tyrosine residues to N-acetylimidazole, together with previous evidence, suggests that: (a) Tyrosine residues 160 and 164, when acetylated, are likely to be responsible for the low binding activity of acetylated hGH. (b) Tyrosine 160 may play a significant role in hGH interaction with lactogenic receptors.

研究了酪氨酸残基乙酰化对人生长激素(hGH)与大鼠肝脏泌乳和促生长受体结合能力的影响。当3.7个酪氨酸和4.8个赖氨酸残基被n -乙酰咪唑乙酰化后,hGH在体内和体外与125i标记的牛生长激素竞争促生长结合位点的能力都大大降低。乙酰化也影响了体外与产乳位点的结合能力。羟胺处理可以去除酪氨酸残基上的o -乙酰基,但不能去除赖氨酸残基上的n -乙酰基,从而恢复了大部分的促生结合活性。同样的处理部分恢复了乳原结合能力。hGH酪氨酸残基对n -乙酰咪唑的反应性,连同先前的证据,表明:(a)酪氨酸残基160和164,当乙酰化时,可能是导致乙酰化hGH结合活性低的原因。(b)酪氨酸160可能在生长激素与乳原受体的相互作用中起重要作用。
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引用次数: 0
Peptides from chiral C alpha,alpha-disubstituted glycines. Crystallographic characterization of conformation of C alpha-methyl, C alpha-isopropylglycine [(alpha Me)Val] in simple derivatives and model peptides. 手性C -二取代甘氨酸生成的肽。C -甲基,C -异丙基甘氨酸[(α Me)Val]在简单衍生物和模型肽中的构象的晶体学表征。
G Valle, M Crisma, C Toniolo, S Polinelli, W H Boesten, H E Schoemaker, E M Meijer, J Kamphuis

The molecular and crystal structures of one derivative and three model peptides (to the pentapeptide level) of the chiral C alpha,alpha-disubstituted glycine C alpha-methyl, C alpha-isopropylglycine [(alpha Me)Val] have been determined by X-ray diffraction. The derivative is mClAc-L-(alpha Me)Val-OH, and the peptides are Z-L-(alpha Me)Val-(L-Ala)2-OMe monohydrate, Z-Aib-L-(alpha Me)Val-(Aib)2-OtBu, and Ac-(Aib)2-L-(alpha Me)Val-(Aib)2OtBu acetonitrile solvate. The tripeptide adopts a type-I beta-turn conformation stabilized by a 1----4N--H...O = C intramolecular H-bond. The tetra- and pentapeptides are folded in regular right-handed 3(10)-helices. All four L-(alpha Me)Val residues prefer phi, psi angles in the right-handed helical region of the conformational map. The results indicate that: (i) the (alpha Me)Val residue is a strong type-I/III beta-turn and helix former, and (ii) the relationship between (alpha Me)Val chirality and helix screw sense is the same as that of C alpha-monosubstituted protein amino-acids. The implications for the use of the (alpha Me)Val residue in designing conformationally constrained analogues of bioactive peptides are briefly discussed.

用x射线衍射测定了手性C α、α -二取代甘氨酸C α -甲基、C α -异丙基甘氨酸[(α - Me)Val]的一个衍生物和三个模型肽的分子和晶体结构(达到五肽水平)。衍生物为mClAc-L-(α Me)Val- oh,多肽为Z-L-(α Me)Val-(L-Ala)2-OMe一水化合物、Z-Aib-L-(α Me)Val-(Aib)2-OtBu和Ac-(Aib)2-L-(α Me)Val-(Aib)2OtBu乙腈溶剂。该三肽采用1----4N—H…稳定的i型β -旋构象。O = C分子内氢键。四肽和五肽折叠成规则的右手3(10)螺旋。所有四个L-(α Me)Val残基都倾向于在构象图的右手螺旋区形成φ, psi角。结果表明:(i) (α Me)Val残基是一个强的i /III型β旋转和螺旋前体;(ii) (α Me)Val手性与螺旋旋感之间的关系与C α -单取代蛋白氨基酸相同。简要讨论了在设计构象约束的生物活性肽类似物中使用(α Me)Val残基的含义。
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引用次数: 0
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International journal of peptide and protein research
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